Proteoglycans (PGs) of normal articular cartilage, which are responsible for its elasticity and compressive stiffness, exist in large aggregates, in which a number of PGs are non-covalently linked to a highly polymerized molecule of hyaluronic acid (HA). Osteoarthritis (OA) is marked by a breakdown in articular cartilage, with loss of PGs, and, in the earliest stages, defective aggregation. The etiology of OA is not well understood, but appears too frequently to be related to mechanical factors. Cartilage may degenerate if the joint is used too little or if it is used excessively. Thus, an optimal level of joint motion and/or load appears to be important in maintaining the health of articular cartilage. We have recently shown that immobilization of the leg of a normal dog and amputation of the ipsilateral paw (which eliminates normal loading of the cartilage from contraction of muscles which stabilize the joint in stance) lead to cartilage atrophy, suppression of PG synthesis and diminished PG aggregation. The changes produced by 6 weeks of immobility were rapidly reversible. Because PGs contribute importantly to the biomechanical integrity of cartilage, however, use of the joint (loading) in the presence of the above changes could be undesirable and lead to chondrocyte damage. We now aim to characterize more completely, and examine the basis for, the degenerative changes in joint cartilage which result from immobilization. PG and HA synthesis will be assayed in tissue culture; catabolism of these molecules will be studied in pulse-chase experiments and correlated with neutral and acid protease activity. A particular aim will be to determine whether use of a recently immobilized joint affects reversibility of the changes induced by disuse, and whether vigorous use of a recently immobilized joint may lead to OA. Finally, because our preliminary studies have indicated that load - and not joint motion alone - is important in maintaining the health of joint cartilage, we will study the effects of static and intermittent compression on normal cartilage in vitro.